WO1997003038A1 - Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkylsilylated derivatives and alkaline iodides, and pharmacological activities thereof - Google Patents

Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkylsilylated derivatives and alkaline iodides, and pharmacological activities thereof Download PDF

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WO1997003038A1
WO1997003038A1 PCT/FR1996/001075 FR9601075W WO9703038A1 WO 1997003038 A1 WO1997003038 A1 WO 1997003038A1 FR 9601075 W FR9601075 W FR 9601075W WO 9703038 A1 WO9703038 A1 WO 9703038A1
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oil
fatty acids
esters
iodized
derivatives
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PCT/FR1996/001075
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French (fr)
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Louis Jung
Yves Ingenbleek
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Louis Jung
Yves Ingenbleek
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Priority to US08/981,931 priority Critical patent/US6124357A/en
Application filed by Louis Jung, Yves Ingenbleek filed Critical Louis Jung
Priority to PL96324383A priority patent/PL185807B1/en
Priority to EP96924964A priority patent/EP0840720B1/en
Priority to EA199800120A priority patent/EA001719B1/en
Priority to AU65234/96A priority patent/AU6523496A/en
Priority to BR9609610-1A priority patent/BR9609610A/en
Priority to RO98-00028A priority patent/RO120337B1/en
Priority to DE69629928T priority patent/DE69629928T2/en
Priority to APAP/P/1998/001180A priority patent/AP874A/en
Priority to AT96924964T priority patent/ATE249414T1/en
Priority to UA98020668A priority patent/UA56142C2/en
Publication of WO1997003038A1 publication Critical patent/WO1997003038A1/en
Priority to BG102234A priority patent/BG63802B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

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  • the subject of the invention is esters of iodized fatty acids and iodized fatty acids and their derivatives, obtained by iodohydrination using aikylsilylated derivatives with alkaline iodides used in the treatment of endemic goiter and the pharmaceutical compositions containing them. They can also be used as contrast compounds in radiology and as a vehicle for chemoembolization.
  • Endemic goiter is a deficiency disease which is one of the most serious public health problems facing the World Health Organization (WHO).
  • Adolescent girls and women of reproductive age are the most exposed and can give birth to a high proportion reaching up to 10% of newborns suffering from a particular form of irreversible mental debility, called endemic cretinism, and considered as the the most daunting medical and social complication. It is universally recognized that the dietary iodine deficit is the primary and largely predominant cause of this nutritional scourge. The geological nature and the geographical environment thus appear as the main determinants of this situation, although certain nutritional factors are incriminated as aggravating secondary causes. The appropriate therapy will therefore consist in supplementing the deficient populations with iodized intakes covering physiological needs.
  • Lipiodol® iodized oil with a delay effect
  • This iodized oil designed as a product contrast in radiology, is made from rare and relatively expensive flaxseed oil (Somnifer papaverum).
  • a new iodized drug is proposed, formed from esters of iodized fatty acids or iodized fatty acids and their derivatives, of pharmaceutical purity, stable, devoid of toxic impurities, totally iodized, not having more double bonds, obtained by the action of an alkylsilylated reagent and an alkali metal iodide on fatty acid esters or fatty acids and having therapeutic properties.
  • methyl esters of iodized fatty acids obtained by an original synthesis from rapeseed oil (Brassica campestris) used as biological fuel for car engines with a very low cost price it is possible to manufacture low cost iodized fatty acid esters making it possible to envisage mass campaigns.
  • the new product ensures better bioavailability and a prolonged therapeutic effect because iodine is fixed on the three fatty acids (oleic acid n-9, linoleic acid n-6 and ⁇ -linolenic acid n-3) - the last two of which are essential - precursors of the three main metabolic pathways of lipids.
  • the administration of our iodized product is offered exclusively by oral route.
  • Hydroiodination with potassium iodide in orthophosphoric acid can also be considered (Organic. Synthesis, vol 9, 66).
  • Organic. Synthesis, vol 9, 66 As specified, inter alia, the German patent N ° C 07 C 69/62 / P 3513 323.8 of 13.4.1985 of W. KUHN et al.,
  • the methods of preparation of iodinated compounds lead to products containing toxic impurities, products that are not very stable in air and light during their preparation and storage.
  • Our preparation method leads in particular to a product with different constituents no longer exhibiting any double bond, a source of instability in particular in the presence of oxidation derivatives and free radicals.
  • Esters of fatty iodized acids prepared by iodohydrination involving aikylsilylated derivatives and an alkaline iodide, object of the invention are in the form of an oily, fluid, light yellow, stable, pharmaceutically pure liquid, with a relatively low cost price.
  • the fatty acid esters used for the preparation of iodinated derivatives involving an alkylsilylated compound and an alkali metal iodide can for example be triglycerides of fatty acids originating from vegetable oils, of the rapeseed oil, flaxseed oil, oil soy, safflower oil, peanut oil, grape seed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil , palm oil and oils of animal origin.
  • the fatty acid esters used can also be mixtures of methyl esters or ethyl esters of fatty acids obtained from vegetable oils, such as rapeseed oil, flaxseed oil, soybean oil, safflower oil. , peanut oil, grape seed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil, palm oil and oils of animal origin.
  • vegetable oils such as rapeseed oil, flaxseed oil, soybean oil, safflower oil.
  • Fatty acids such as oleic acid, linoleic acid, ⁇ -linolenic acid, erucic acid, arachidonic acid, ricinolic acid can also be used as raw materials.
  • the process for obtaining esters of iodized fatty acids or of iodized fatty acids consists in reacting an alkaline iodide with a halurealkylsilylated in organic medium giving rise in the presence of water to hydrodic acid in situ reacting either with the ester or esters of fatty acids, or with fatty acids.
  • esters of iodized fatty acids or of iodized fatty acids consists, for example, in reacting sodium iodide with chloride of trimethylsilyl or trimethylchlorosilane in acetonitrile followed by the action of water and the addition of either esters of unsaturated fatty acids or of unsaturated fatty acids.
  • iodohydrination of fatty acid esters can be carried out according to the following reaction:
  • the procedure for example for unsaturated fatty acid esters, is as follows: to a solution of 107.1 g of sodium iodide in 550 ml of acetonitrile is added under a nitrogen atmosphere and at 0 ° C., 89.25 ml of trimethylchlorosilane (or trimethylsilyl chloride). After the total addition of the trimethylchlorosilane, 6.65 ml of water is added dropwise. Then a solution of 70 g of unsaturated methyl or ethyl esters of rapeseed oil fatty acids is added. After 24 hours of reaction with stirring, the reaction is then stopped with 700 ml of water. The extraction is carried out with ether.
  • the organic phase is washed several times with a 10 percent sodium thiosulfate solution and then several times with water. It is dried over anhydrous sodium sulphate and the ether is evaporated at a temperature of 90 ° C. under 16 mm of Hg in order to remove the remains of silica ether. The residue is brown.
  • the esters of iodized fatty acids, dissolved in ether, are then discolored on charcoal and then filtered through alumina in order to remove the peroxides.
  • the ether is evaporated off and the traces of solvent are removed using a vane pump.
  • the mixture of iodized fatty acid esters obtained is golden yellow and has good fluidity.
  • This mixture can be characterized by 1 H NMR and 13C NMR spectrometry.
  • This method of synthesis of iodized fatty acid esters has been carried out on larger quantities.
  • Other water-immiscible solvents can be used.
  • the insolubility of sodium chloride in acetonitrile allows the total displacement of the reaction towards the formation of trimethylsilyl iodide.
  • This reaction is exothermic and allows the generation of hydroiodic acid and trimethylsilyl hydroxyl.
  • the product secondary SiM ⁇ 3 ⁇ H is eliminated after the iodohydrination reaction by simple evaporation under reduced pressure and washing with water. The iodohydrination reaction is followed visually by discoloration of the solution.
  • a 1 H NMR spectrum of the esters of iodized fatty acids in rapeseed oil makes it possible, by comparison with the spectrum of esters of non-iodized fatty acids in rapeseed oil, to verify the disappearance of the ethylenic protons. In addition, this makes it possible to control the absence of traces of diethyl ether solvent and of silica ether. Furthermore, a 13c NMR spectrum makes it possible to verify the disappearance of the carbons carrying the unsaturations.
  • the stability study is carried out by 1 H NMR, by thin layer chromatography and by an assay of iodine fixed on the fatty acid esters or on the fatty acids.
  • 1 H NMR spectra were performed after 2 months, 3 months and 8 months of storage at temperature 20-22 ° C protected from light. They are all three identical to the spectrum obtained during manufacture.
  • Thin layer chromatography sica gel plate GF 254 - mobile phase: diethyl ether / hexane 1:20 - examination under ultraviolet light at 254 nm and after spraying with a solution of phosphomolybdic acid R at 10 percent m / V in alcohol and heating the plate at 120 ° C.
  • the esters of iodized fatty acids were analyzed: the 1 H NMR spectrum was found to be identical to that of a freshly synthesized oil and the thin layer chromatography gave spots identical to those of the esters of freshly synthesized iodized fatty acids, and did not reveal no degradation product.
  • Tolerance test in rats before administering the mixture of iodized fatty acid esters of rapeseed oil to goitreous subjects, a tolerance test on the mixture of iodized esters is carried out on adult male rats 'about 300 g. Each test group consists of 5 rats which each receive an oral administration of 0.5 ml of a mixture of iodized fatty acid esters of rapeseed oil.
  • the rats are kept under observation. After one week, the behavior and general condition of the rats in each test group are normal and identical to those in the control group.
  • iodized products prepared according to the method described above are used as medicaments in general, for example as anti-goiter in the pure state or in combination with suitable excipients in the form of drinkable or ingestible liquid, capsules or ampoules by example.
  • iodized products can also be used as drugs by general or topical route, for example as contrast agents or as anti-inflammatory drugs in rheumatoid therapeutics.
  • These products can be used as drugs by general route or by local vascular route in the treatment of certain cancers by chemoembolization consisting in administering an anticancer cancer emulsified in esters of iodized fatty acids which act as vectors for lipophilic tumor cells.

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Abstract

Iodinated fatty acid esters, iodinated fatty acids and fluid pharmaceutical-grade stable derivatives thereof are produced by iodohydrination in an organic medium using alkylsilylated derivatives, e.g. trimethylsilyl chloride or trimethylchlorosilane, that react with an alkaline iodide such as sodium iodide, whereafter hydroiodic acid is formed in situ by exposure to water and the hydroiodic acid is reacted, e.g., with fatty acid esters and particularly rapeseed oil fatty acid methyl esters that may be used as a biofuel for gasoline engines to provide a low-cost product, and are used therapeutically, in particular for treating goitre linked to iodine deficiency.

Description

Esters d'acides gras iodés, acides gras iodés et leurs dérivés, obtenus par iodohydrination, faisant intervenir des dérivés aikylsilylés avec des iodures alcalins et leurs activités pharmacologiquesEsters of iodized fatty acids, iodized fatty acids and their derivatives, obtained by iodohydrination, involving aikylsilylated derivatives with alkaline iodides and their pharmacological activities
L'invention a pour objet des esters d'acides gras iodés et des acides gras iodés et leurs dérivés, obtenus par iodohydrination faisant intervenir des dérivés aikylsilylés avec des iodures alcalins utilisés dans le traitement du goitre endémique et les compositions pharmaceutiques les renfermant. II peuvent également être utilisés comme composés de contraste en radiologie et comme véhicule de chimioembolisation. Le goitre endémique est une maladie carentielle qui constitue un des plus graves problèmes de santé publique auxquels l'Organisation Mondiale de la Santé (OMS) soit confronté. Selon les indications officielles de l'OMS, un milliard d'individus, soit 20 % de la population mondiale est touché par le déficit iodé, principalement dans les pays en voie de développement (HETZEL B.S., POTTER B.J. and DULBERG E.M. The iodine deficiency disorders : nature, pathogenesis and epidemiology. World Rev. Nutr. Diet. 62 : 59-119 (1990)). La quasi totalité de ces pays est concernée avec des degrés de prévalence très variables. Dans les régions les plus sévèrement affectées, on peut dénombrer jusqu'à 80 % de sujets souffrant de dysfonctionnements thyroïdiens : ceux-ci se traduisent par l'apparition d'une hypertrophie glandulaire inesthétique pouvant évoluer vers une hypothyroïdie secondaire avec troubles neurologiques. Les adolescentes et les femmes en âge de procréer sont les plus exposées et peuvent donner naissance à une proportion élevée atteignant jusqu'à 10 % des nouveaux-nés souffrant d'une forme particulière de débilité mentale irréversible, appelée crétinisme endémique, et considérée comme la complication médicale et sociale la plus redoutable. II est universellement reconnu que le déficit alimentaire en iode est la cause première et largement prédominante de ce fléau nutritionnel. La nature géologique et l'environnement géographique apparaissent ainsi comme les déterminants principaux de cette situation, bien que certains facteurs alimentaires soient incriminés comme causes secondaires aggravantes. La thérapeutique appropriée consistera donc à supplementer les populations déficientes par des apports iodés couvrant les besoins physiologiques.The subject of the invention is esters of iodized fatty acids and iodized fatty acids and their derivatives, obtained by iodohydrination using aikylsilylated derivatives with alkaline iodides used in the treatment of endemic goiter and the pharmaceutical compositions containing them. They can also be used as contrast compounds in radiology and as a vehicle for chemoembolization. Endemic goiter is a deficiency disease which is one of the most serious public health problems facing the World Health Organization (WHO). According to official WHO indications, one billion people, or 20% of the world's population, are affected by the iodine deficit, mainly in developing countries (HETZEL BS, POTTER BJ and DULBERG EM The iodine deficiency disorders : nature, pathogenesis and epidemiology. World Rev. Nutr. Diet. 62: 59-119 (1990)). Almost all of these countries are affected with widely varying degrees of prevalence. In the most severely affected regions, up to 80% of people suffering from dysfunction can be counted thyroid: these result in the appearance of an unsightly glandular enlargement which can progress to secondary hypothyroidism with neurological disorders. Adolescent girls and women of reproductive age are the most exposed and can give birth to a high proportion reaching up to 10% of newborns suffering from a particular form of irreversible mental debility, called endemic cretinism, and considered as the the most formidable medical and social complication. It is universally recognized that the dietary iodine deficit is the primary and largely predominant cause of this nutritional scourge. The geological nature and the geographical environment thus appear as the main determinants of this situation, although certain nutritional factors are incriminated as aggravating secondary causes. The appropriate therapy will therefore consist in supplementing the deficient populations with iodized intakes covering physiological needs.
Théoriquement, cet objectif est aisé à atteindre. Cependant, l'expérience des dernières décennies a montré que les véhicules traditionnels de supplémentation iodée (eau potable, sel de cuisine, farines boulangères) rencontrent dans les régions (sub)-tropicales des difficultés majeures de diffusion, liées aux conditions de transport, de conservation, de consommation. En effet, l'iode est administré sous forme d'iodure ou d'iodate de sodium ou de potassium, libérant l'halogène sous une forme non stockable dans les tissus adipeux. Une prise quotidienne du véhicule iodé est donc nécessaire pendant des années. Les bénéfices nutritionnels sont irréguliers et lents à obtenir, et cette forme de supplémentation ne permet pas de remédier rapidement aux problèmes urgents rencontrés dans les régions de haute prévalence. II existe également une huile iodé à effet-retard, appelée Lipiodol®(Société Guerbet) et quiy administrée sous une dose orale ou parentérale annuelle unique, a démontré des effets préventifs et thérapeutiques anti-goitreux. Cette huile iodée, conçue comme produit de contraste en radiologie, est fabriquée à partir d'huile d'oeillette (Somnifer papaverum) rare et relativement chère. Bien que la bonne tolérance et les vertus curatives du Lipiodol® soient connues depuis longtemps, ce produit ne s'est pas imposé comme outil d'éradication massive en raison d'un coût relativement élevé en regard des immenses besoins du Tiers-Monde.Theoretically, this objective is easy to achieve. However, the experience of recent decades has shown that traditional iodine supplementation vehicles (drinking water, cooking salt, baking flours) encounter in (sub) -tropical regions major difficulties of diffusion, linked to transport conditions, conservation, consumption. In fact, iodine is administered in the form of iodide or iodate of sodium or potassium, releasing the halogen in a form which cannot be stored in adipose tissue. A daily intake of the iodized vehicle is therefore necessary for years. The nutritional benefits are irregular and slow to obtain, and this form of supplementation does not make it possible to quickly remedy the urgent problems encountered in regions of high prevalence. There is also an iodized oil with a delay effect, called Lipiodol® (Guerbet Company) and which administered there under a single oral or parenteral annual dose, has demonstrated preventive and therapeutic anti-goiter effects. This iodized oil, designed as a product contrast in radiology, is made from rare and relatively expensive flaxseed oil (Somnifer papaverum). Although the good tolerance and healing properties of Lipiodol® have been known for a long time, this product has not established itself as a tool for mass eradication because of a relatively high cost compared to the immense needs of the Third World.
Notre invention vise à supprimer cet handicap : il est proposé un nouveau médicament iodé, formé d'esters d'acides gras iodés ou acides gras iodés et leurs dérivés, de pureté pharmaceutique, stables, dépourvus d'impuretés toxiques, totalement iodés, ne présentant plus de doubles liaisons, obtenus par action d'un réactif alkylsilylé et d'un iodure alcalin sur des esters d'acides gras ou des acides gras et présentant des propriétés thérapeutiques.Our invention aims to eliminate this handicap: a new iodized drug is proposed, formed from esters of iodized fatty acids or iodized fatty acids and their derivatives, of pharmaceutical purity, stable, devoid of toxic impurities, totally iodized, not having more double bonds, obtained by the action of an alkylsilylated reagent and an alkali metal iodide on fatty acid esters or fatty acids and having therapeutic properties.
Par exemple à partir d'esters méthyliques d'acides gras iodés obtenus pas une synthèse originale à partir d'huile de colza (Brassica campestris) utilisés comme carburant biologique pour les moteurs de voitures d'un prix de revient très faible, il est possible de fabriquer des esters d'acides gras iodés de faible coût permettant d'envisager des campagnes de masse. Le nouveau produit assure une meilleure biodisponibilité et un effet thérapeutique prolongé car l'iode est fixé sur les trois acides gras (acide oléique n-9, acide linoléique n-6 et acide α- linolénique n-3) - dont les deux derniers sont essentiels - précurseurs des trois principales voies métaboliques des lipides. En vue de prévenir les risques de contamination virale par voie sanguine (hépatites B et C, VIH) l'administration de notre produit iodé est proposée exclusivement par voie orale.For example, from methyl esters of iodized fatty acids obtained by an original synthesis from rapeseed oil (Brassica campestris) used as biological fuel for car engines with a very low cost price, it is possible to manufacture low cost iodized fatty acid esters making it possible to envisage mass campaigns. The new product ensures better bioavailability and a prolonged therapeutic effect because iodine is fixed on the three fatty acids (oleic acid n-9, linoleic acid n-6 and α-linolenic acid n-3) - the last two of which are essential - precursors of the three main metabolic pathways of lipids. In order to prevent the risks of viral contamination by blood (hepatitis B and C, HIV) the administration of our iodized product is offered exclusively by oral route.
Plusieurs méthodes ont déjà été décrites pour la transformation d'acides gras insaturés ou d'esters d'acides gras insaturés en dérivés saturés iodés. L'acide oléique peut subir une hydrobromation suivie d'une substitution nucléophile par l'iodure de potassium après action de l'acide bromhydrique. (J.F. LANE and H.W. HEINE ; On cyclic Intermediates in Substitution Reactions. I. The Alkaline Hydrolysis of Some Aliphatic Bromoacids. J. Am. Chem. Soc. 1951 , 73, 1348 -1350). L'huile d'olive refroidie au voisinage du point de prise en masse est saturée directement d'acide iodhydrique. D'autres acides gras ont été envisagés. (A. GUERBET, A. GIBAUD, G. TILLY, R. JOUSSOT, V. LOTH et M. GUERBET ; Monoiodostéarate d'éthyle. Préparation et caractères analytiques. Ann. pharm. fr., 1965, 23, N°11 , 663-671). L'iodation directe par l'acide iodhydrique est également réalisée en utilisant des substances déshydratantes tels les acides polyphosphoriques, le pentoxyde de phosphore (W. KUHN, H. HARTNER, F. SCHINDLER, I. SANDNER et K. HERING ; brevet allemand P 35 13 322.6/C 07 C 69/62, 1985). L'hydroiodation peut également être réalisée par de l'iode en présence d'alumine générant de l'acide iodhydrique (L. J. STEWART, D. GRAY, R. M. PAGNI and G. W. KABALKA ; A Convenient method for the addition of Hl to unsaturated hydrocarbons using I2 on AI2O3, Tetrahedron Lett, 1987, Vol. 28, N° 39, 4497-4498). L'hydroiodation a également été réalisée au moyen du complexe bore-N.N-diéthylamine faisant intervenir le triiodure de bore. (CH. KISHAN REDDY and M. PERIASAMY ; A new, simple procédure for the génération and addition of Hl to alkenes and alkynes using BI3 : N,N-diethylanilline complex and acetic acid. Tetrahedron Lett., 1990, Vol. 31 , N°13, 1919-1920). L'hydroiodation par l'iodure de potassium dans l'acide orthophosphorique peut également être envisagée (Organic. Synthesis, vol 9, 66). Comme le précise, entre autres, le brevet allemand N° C 07 C 69/62 / P 3513 323.8 du 13.4.1985 de W. KUHN et coll., les méthodes de préparation de composés iodés conduisent à des produits contenant des impuretés toxiques, des produits peu stables à l'air et à la lumière lors de leur préparation et de leur conservation. Notre méthode de préparation conduit en particulier à un produit aux différents constituants ne présentant plus aucune double liaison, source d'instabilité en particulier en présence de dérivés d'oxydation et de radicaux libres. Les esters d'acides iodés gras préparés par iodohydrination faisant intervenir des dérivés aikylsilylés et un iodure alcalin, objet de l'invention, se présentent sous forme d'un liquide huileux, fluide, jaune clair, stable, pharmaceutiquement pur, d'un prix de revient relativement faible.Several methods have already been described for the transformation of unsaturated fatty acids or of esters of unsaturated fatty acids into iodinated saturated derivatives. Oleic acid can undergo hydrobromination followed by nucleophilic substitution with potassium iodide after the action of hydrobromic acid. (JF LANE and HW HEINE; On cyclic Intermediates in Substitution Reactions. I. The Alkaline Hydrolysis of Some Aliphatic Bromoacids. J. Am. Chem. Soc. 1951, 73, 1348 -1350). The olive oil cooled near the setting point is directly saturated with hydroiodic acid. Other fatty acids have been considered. (A. GUERBET, A. GIBAUD, G. TILLY, R. JOUSSOT, V. LOTH and M. GUERBET; Ethyl monoiodostearate. Preparation and analytical characteristics. Ann. Pharm. Fr., 1965, 23, N ° 11, 663-671). Direct iodization with hydroiodic acid is also carried out using dehydrating substances such as polyphosphoric acids, phosphorus pentoxide (W. KUHN, H. HARTNER, F. SCHINDLER, I. SANDNER and K. HERING; German patent P 35 13 322.6 / C 07 C 69/62, 1985). Hydroiodination can also be carried out with iodine in the presence of alumina generating hydroiodic acid (LJ STEWART, D. GRAY, RM PAGNI and GW KABALKA; A Convenient method for the addition of Hl to unsaturated hydrocarbons using I2 on AI2O3, Tetrahedron Lett, 1987, Vol. 28, No. 39, 4497-4498). Hydroiodination was also carried out using the boron-NN-diethylamine complex involving boron triiodide. (CH. KISHAN REDDY and M. PERIASAMY; A new, simple procedure for the generation and addition of Hl to alkenes and alkynes using BI3: N, N-diethylanilline complex and acetic acid. Tetrahedron Lett., 1990, Vol. 31, N ° 13, 1919-1920). Hydroiodination with potassium iodide in orthophosphoric acid can also be considered (Organic. Synthesis, vol 9, 66). As specified, inter alia, the German patent N ° C 07 C 69/62 / P 3513 323.8 of 13.4.1985 of W. KUHN et al., The methods of preparation of iodinated compounds lead to products containing toxic impurities, products that are not very stable in air and light during their preparation and storage. Our preparation method leads in particular to a product with different constituents no longer exhibiting any double bond, a source of instability in particular in the presence of oxidation derivatives and free radicals. Esters of fatty iodized acids prepared by iodohydrination involving aikylsilylated derivatives and an alkaline iodide, object of the invention are in the form of an oily, fluid, light yellow, stable, pharmaceutically pure liquid, with a relatively low cost price.
Les esters d'acides gras utilisés pour la préparation des dérivés iodés faisant intervenir un composé alkylsilylé et un iodure alcalin peuvent par exemple être des triglycérides d'acides gras provenant d'huiles végétales, du type huile de colza, huile d'oeillette, huile de soja, huile de carthame, huile d'arachides, huile de pépins de raisin, huile de tournesol, huile de lin, huile de maïs, huile d'olive, huile de sésame, huile de germes de blé, huile de noix de coco, huile de palme et huiles d'origine animale.The fatty acid esters used for the preparation of iodinated derivatives involving an alkylsilylated compound and an alkali metal iodide can for example be triglycerides of fatty acids originating from vegetable oils, of the rapeseed oil, flaxseed oil, oil soy, safflower oil, peanut oil, grape seed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil , palm oil and oils of animal origin.
Les esters d'acides gras utilisés peuvent également être, des mélanges d'esters méthyliques ou d'esters éthyiiques d'acides gras provenant d'huiles végétales, du type huile de colza, huile d'oeillette, huile de soja, huile de carthame, huile d'arachides, huile de pépins de raisin, huile de tournesol, huile de lin, huile de maïs, huile d'olive, huile de sésame, huile de germe de blé, huile de noix de coco, huile de palme et huiles d'origine animale. Utiliser une matière première pour la synthèse des esters méthyliques d'acides gras provenant de l'huile de colza, utilisés comme carburant biologique pour moteur de voitures d'un prix de revient faible est particulièrement intéressante pour des productions importantes de médicaments.The fatty acid esters used can also be mixtures of methyl esters or ethyl esters of fatty acids obtained from vegetable oils, such as rapeseed oil, flaxseed oil, soybean oil, safflower oil. , peanut oil, grape seed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil, palm oil and oils of animal origin. Using a raw material for the synthesis of methyl esters of fatty acids from rapeseed oil, used as biological fuel for car engines at low cost is particularly advantageous for large production of drugs.
Les acides gras du type acide oléique, acide linoléique, acide α- linolénique, acide érucique, acide arachidonique, acide ricinolique peuvent également être utilisés comme matières premières. Le procédé pour l'obtention d'esters d'acides gras iodés ou d'acides gras iodés consiste à faire réagir un iodure alcalin avec un halogénurealkylsilylé en milieu organique donnant naissance en présence d'eau à de l'acide iodhydrique in situ réagissant soit avec l'ester ou les esters d'acides gras, soit avec les acides gras. L'obtention d'esters d'acides gras iodés ou d'acides gras iodés consiste par exemple à faire réagir de l'iodure de sodium sur du chlorure de trimethylsilyle ou trimethylchlorosilane dans de l'acétonitrile suivie de l'action de l'eau et d'une addition soit d'esters d'acides gras insaturés, soit d'acides gras insaturés..Fatty acids such as oleic acid, linoleic acid, α-linolenic acid, erucic acid, arachidonic acid, ricinolic acid can also be used as raw materials. The process for obtaining esters of iodized fatty acids or of iodized fatty acids consists in reacting an alkaline iodide with a halurealkylsilylated in organic medium giving rise in the presence of water to hydrodic acid in situ reacting either with the ester or esters of fatty acids, or with fatty acids. Obtaining esters of iodized fatty acids or of iodized fatty acids consists, for example, in reacting sodium iodide with chloride of trimethylsilyl or trimethylchlorosilane in acetonitrile followed by the action of water and the addition of either esters of unsaturated fatty acids or of unsaturated fatty acids.
L'iodohydrination d'esters d'acides gras peut se faire selon la réaction suivante :The iodohydrination of fatty acid esters can be carried out according to the following reaction:
CH3CN H2O (1)CH3CN H2O (1)
Nal + SiMβ3CI ->* NaCl + SiMθ3l — ^ SiMβ3θH + Hl —>" iodohydrineNal + SiMβ3CI -> * NaCl + SiMθ3l - ^ SiMβ3θH + Hl ->"iodohydrin
(1) esters d'acides gras ou acides gras(1) fatty acid esters or fatty acids
Le mode opératoire par exemple pour des esters insaturés d'acides gras est le suivant : à une solution de 107,1 g d'iodure de sodium dans 550 ml d'acétonitrile, on ajoute sous atmosphère d'azote et à 0°C, 89,25 ml de triméthylchlorosilane(ou chlorure de trimethylsilyle). Après addition totale du trimethylchlorosilane, on ajoute au goutte à goutte 6,65 ml d'eau. Ensuite est ajoutée une solution de 70 g d'esters méthyliques ou éthyliques insaturés d'acides gras d'huile de colza. Après 24 heures de réaction sous agitation, la réaction est ensuite stoppée avec 700 ml d'eau. L'extraction est réalisée avec de l'éther. La phase organique est lavée plusieurs fois avec une solution de thiosulfate de sodium à 10 pour cent puis plusieurs fois à l'eau. Elle est séchée sur sulfate de sodium anhydre et l'éther est évaporé à une température de 90°C sous 16 mm de Hg afin d'éliminer les restes d'éther de silice. Le résidu est brun. Les esters d'acides gras iodés, dissous dans l'éther, sont ensuite décolorés sur du charbon puis filtrés sur de l'alumine afin d'éliminer les peroxydes. L'éther est évaporé et les traces de solvant sont éliminées à la pompe à palette. Le mélange d'esters d'acides gras iodés obtenus est jaune doré et présente une bonne fluidité. Ce mélange peut être caractérisé par spectrométrie 1 H NMR et 13C NMR. Cette méthode de synthèse d'esters d'acides gras iodés a été réalisée sur des quantités plus importantes. D'autres solvants non miscibles à l'eau peuvent être utilisés. L'insolubilité du chlorure de sodium dans l'acétonitrile permet le déplacement total de la réaction vers la formation d'iodure de trimethylsilyle. Cette réaction est exothermique et permet la génération d'acide iodhydrique et d'hydroxyle de trimethylsilyle. Le produit secondaire SiMβ3θH est éliminé après la réaction d'iodohydrination par simple évaporation sous pression réduite et lavage à l'eau. La réaction d'iodohydrination est suivie visuellement par une décoloration de la solution. Le thiosulfate de sodium permet l'élimination de l'iode présent sous forme oxydée. Pour le produit final plus aucun signal en RMN du proton et en RMN carbone 13 ne correspond à un système ethylenique. D'autre part aucun produit de dégradation n'apparaît en RMN du proton. Caractéristiques des esters des acides gras iodés de l'huile de colza :The procedure, for example for unsaturated fatty acid esters, is as follows: to a solution of 107.1 g of sodium iodide in 550 ml of acetonitrile is added under a nitrogen atmosphere and at 0 ° C., 89.25 ml of trimethylchlorosilane (or trimethylsilyl chloride). After the total addition of the trimethylchlorosilane, 6.65 ml of water is added dropwise. Then a solution of 70 g of unsaturated methyl or ethyl esters of rapeseed oil fatty acids is added. After 24 hours of reaction with stirring, the reaction is then stopped with 700 ml of water. The extraction is carried out with ether. The organic phase is washed several times with a 10 percent sodium thiosulfate solution and then several times with water. It is dried over anhydrous sodium sulphate and the ether is evaporated at a temperature of 90 ° C. under 16 mm of Hg in order to remove the remains of silica ether. The residue is brown. The esters of iodized fatty acids, dissolved in ether, are then discolored on charcoal and then filtered through alumina in order to remove the peroxides. The ether is evaporated off and the traces of solvent are removed using a vane pump. The mixture of iodized fatty acid esters obtained is golden yellow and has good fluidity. This mixture can be characterized by 1 H NMR and 13C NMR spectrometry. This method of synthesis of iodized fatty acid esters has been carried out on larger quantities. Other water-immiscible solvents can be used. The insolubility of sodium chloride in acetonitrile allows the total displacement of the reaction towards the formation of trimethylsilyl iodide. This reaction is exothermic and allows the generation of hydroiodic acid and trimethylsilyl hydroxyl. The product secondary SiMβ3θH is eliminated after the iodohydrination reaction by simple evaporation under reduced pressure and washing with water. The iodohydrination reaction is followed visually by discoloration of the solution. Sodium thiosulfate allows the elimination of iodine present in oxidized form. For the final product, no more proton NMR and carbon 13 NMR signals correspond to an ethylene system. On the other hand, no degradation product appears in NMR of the proton. Characteristics of the iodized fatty acid esters of rapeseed oil:
Résonance Magnétique Nucléaire du proton (RMNl H) et du carbone 13 (RMN13C). Un spectre RMN1 H des esters des acides gras iodés de l'huile de colza permet, par comparaison avec ie spectre des esters des acides gras non iodés de l'huile de colza, de vérifier la disparition des protons éthyléniques. De plus, cela permet de contrôler l'absence de traces de diéthyléther solvant et d'éther de silice. Par ailleurs, un spectre RMN 13c permet de vérifier la disparition des carbones portant les insaturations.Proton Nuclear Magnetic Resonance (1 H NMR) and carbon 13 ( 3 C NMR). A 1 H NMR spectrum of the esters of iodized fatty acids in rapeseed oil makes it possible, by comparison with the spectrum of esters of non-iodized fatty acids in rapeseed oil, to verify the disappearance of the ethylenic protons. In addition, this makes it possible to control the absence of traces of diethyl ether solvent and of silica ether. Furthermore, a 13c NMR spectrum makes it possible to verify the disappearance of the carbons carrying the unsaturations.
Les spectres RMNl H obtenus pour plusieurs productions d'esters éthyliques d'acides gras iodés d'huile de colza sont identiques. Aucun spectre ne révèle la présence de diéthyléther ou d'éther de silice. • Spectre RMNl H des esters éthyliques d'acide gras iodés [RMNl H (CDCI3) sur 200 MHz] : 0,89 ppm (3H, m,CH3), 1 ,20-2,00 ppm (m, CH2 des chaînes et CH.3CH2O), 2,3 ppm (2H, t, CH2-COOEt), 4,2 ppm (m, CHI, CH2-OOC)The 1 H NMR spectra obtained for several productions of ethyl esters of iodized fatty acids from rapeseed oil are identical. No spectrum reveals the presence of diethyl ether or silica ether. • 1 H NMR spectrum of iodinated fatty acid ethyl esters [1 H NMR (CDCI3) on 200 MHz): 0.89 ppm (3H, m, CH3), 1.20-2.00 ppm (m, CH2 of the chains and CH.3CH2O), 2.3 ppm (2H, t, CH2-COOEt), 4.2 ppm (m, CHI, CH2-OOC)
• Spectre RMN13Q des esters éthyliques d'acides gras iodés : RMN 13C (CDCI3) sur 200 MHz] : 14 ppm (ÇH3 en bout de chaîne et ÇH3CH2O), 28-29 ppm (Ç_HI), 22-24,30-31,34 ppm (ÇH2 des chaînes), 39-41 ppm (ÇH2-CHI), 60 ppm ( ÇH2-O), 173 ppm (Ç_CO).• 13N NMR spectrum of ethyl esters of iodized fatty acids: 1 3 C NMR (CDCI3) on 200 MHz]: 14 ppm (ÇH3 at the end of the chain and ÇH3CH2O), 28-29 ppm (Ç_HI), 22-24,30- 31.34 ppm (ÇH2 of the chains), 39-41 ppm (ÇH2-CHI), 60 ppm (ÇH2-O), 173 ppm (Ç_CO).
Le spectre d'absorption dans l'infrarouge (NaCl) présente les bandes caractéristiques suivantes : Y (C=0 ester) à 1740 cm-1 ; γ (CH saturé) à 2850 cm"1 , γ (CH saturé) à 2950 cm"1The infrared absorption spectrum (NaCl) has the following characteristic bands: Y (C = 0 ester) at 1740 cm -1 ; γ (saturated CH) at 2850 cm "1 , γ (saturated CH) to 2950 cm " 1
•Spectre RMNl H des esters méthyliques d'acides gras iodés [RMNl H (CDCI3) sur 200 MHz] : 0,89 ppm (3H, m, CH3), 1,25 - 1 ,30 ppm (m, CH2 des chaînes), 1 ,60 - 1,80 ppm (m, CH2) 2,3 ppm (2H, t, CH2-COO), 3,66 ppm (3H,s, CH3-OOC), 4, 12 ppm (m, CHI). spectre RMN13C des esters méthyliques d'acides gras iodés [RMN13C (CDCI3) sur 200 MHz] : 14 ppm (ÇH3 en bout de chaîne), 28-29 ppm (Ç_HI), 22 - 24, 31 - 34 ppm (ÇH2 des chaînes), 38-41 ppm (ÇH2-CHI), 51 ppm (ÇH3-O), 173 ppm (ÇOO). Stabilité : Les produits iodés étant en général des substances instables, il est nécessaire de s'assurer de la stabilité des esters d'acides gras iodés ou/et des acides gras iodés. L'étude de stabilité est réalisée par RMN1H, par chromatographie sur couche mince et par un dosage de l'iode fixé sur les esters d'acides gras ou sur les acides gras. Des spectres RMN1H ont été réalisés après 2 mois, 3 mois et 8 mois de conservation à température 20-22°C à l'abri de la lumière. Ils sont tous les trois identiques au spectre obtenu lors de la fabrication. La chromatographie sur couche mince (plaque gel de silice GF 254 - phase mobile : diéthyléther/hexane 1 : 20 - examen sous lumière ultraviolette à 254 nm et après pulvérisation d'une solution d'acide phosphomolybdique R à 10 pour cent m/V dans l'alcool et chauffage de la plaque à 120°C pendant 5 min) donne des taches observées identiques quant à leurs intensités et à leurs positions pour le produit fraîchement préparé et ceux conservés durant 8 mois. Stabilité des esters d'acides gras iodés de l'huile de colza après emploi en thérapeutique sur le terrain : le mélange des esters d'acides gras iodés de l'huile de colza a fait l'objet d'une étude sur l'homme en Afrique, dans une zone de goitre endémique. Lors de cette étude, les esters iodés ont été soumis à des conditions extrêmes (transport, exposition pendant plusieurs heures à la lumière et à des températures de l'ordre de 45 °C). Au bout de deux semaines d'études, les esters d'acides gras iodés ont été analysés : le spectre RMN1H s'est avéré identique à celui d'une huile fraîchement synthétisée et la chromatographie sur couche mince donne des spots identiques à ceux des esters d'acides gras iodés fraîchement synthétisés, et ne révèle aucun produit de dégradation.• 1 H NMR spectrum of iodinated fatty acid methyl esters [1 H NMR (CDCI3) on 200 MHz): 0.89 ppm (3H, m, CH3), 1.25 - 1.30 ppm (m, CH2 of the chains) , 1.60 - 1.80 ppm (m, CH2) 2.3 ppm (2H, t, CH2-COO), 3.66 ppm (3H, s, CH3-OOC), 4.12 ppm (m, CHI ). 13 C NMR spectrum of methyl esters of iodized fatty acids [ 3 C NMR (CDCI3) at 200 MHz): 14 ppm (ÇH3 at the end of the chain), 28-29 ppm (Ç_HI), 22 - 24, 31 - 34 ppm (ÇH2 chains), 38-41 ppm (ÇH2-CHI), 51 ppm (ÇH3-O), 173 ppm (ÇOO). Stability: Since iodized products are generally unstable substances, it is necessary to ensure the stability of the esters of iodized fatty acids and / or iodized fatty acids. The stability study is carried out by 1 H NMR, by thin layer chromatography and by an assay of iodine fixed on the fatty acid esters or on the fatty acids. 1 H NMR spectra were performed after 2 months, 3 months and 8 months of storage at temperature 20-22 ° C protected from light. They are all three identical to the spectrum obtained during manufacture. Thin layer chromatography (silica gel plate GF 254 - mobile phase: diethyl ether / hexane 1:20 - examination under ultraviolet light at 254 nm and after spraying with a solution of phosphomolybdic acid R at 10 percent m / V in alcohol and heating the plate at 120 ° C. for 5 min) gives identical spots observed as regards their intensities and their positions for the freshly prepared product and those stored for 8 months. Stability of iodized fatty acid esters of rapeseed oil after therapeutic use in the field: the mixture of iodized fatty acid esters of rapeseed oil has been the subject of a study in humans in Africa, in an endemic goiter zone. During this study, the iodized esters were subjected to extreme conditions (transport, exposure for several hours to light and to temperatures of the order of 45 ° C). After two weeks of study, the esters of iodized fatty acids were analyzed: the 1 H NMR spectrum was found to be identical to that of a freshly synthesized oil and the thin layer chromatography gave spots identical to those of the esters of freshly synthesized iodized fatty acids, and did not reveal no degradation product.
Essai de tolérance chez le rat : avant d'administrer le mélange d'esters d'acides gras iodés de l'huile de colza à des sujets goitreux, un essai de tolérance de mélange d'esters iodés est effectué sur des rats mâles adultes d'environ 300 g. Chaque groupe test est constitué de 5 rats qui reçoivent chacun une administration orale de 0,5 ml de mélange d'esters d'acides gras iodés d'huile de colza.Tolerance test in rats: before administering the mixture of iodized fatty acid esters of rapeseed oil to goitreous subjects, a tolerance test on the mixture of iodized esters is carried out on adult male rats 'about 300 g. Each test group consists of 5 rats which each receive an oral administration of 0.5 ml of a mixture of iodized fatty acid esters of rapeseed oil.
Les rats sont gardés en observation. Au bout d'une semaine, le comportement et l'état général des rats de chaque groupe test sont normaux et identiques à ceux du groupe témoin.The rats are kept under observation. After one week, the behavior and general condition of the rats in each test group are normal and identical to those in the control group.
Les produits iodés préparés selon la méthode décrite précédemment sont utilisés comme médicaments par voie générale, par exemple comme anti-goitreux à l'état pur ou en combinaison avec des excipients appropriés sous forme de liquide buvable ou ingérable, de gélules ou d'ampoules par exemple.The iodized products prepared according to the method described above are used as medicaments in general, for example as anti-goiter in the pure state or in combination with suitable excipients in the form of drinkable or ingestible liquid, capsules or ampoules by example.
Ces produits iodés peuvent également être utilisés comme médicaments par voie générale ou topique, par exemple comme produits de contraste ou comme antiinflammatoires en thérapeutiques rhumatoïdes. Ces produits peuvent être utilisés comme médicaments par voie générale ou par voie vasculaire locale dans le traitement de certains cancers par chimioembolisation consistant à administrer un anticancéreux émulsionné dans des esters d'acides gras iodés qui jouent le rôle de vecteurs pour les cellules lipophiles tumorales. These iodized products can also be used as drugs by general or topical route, for example as contrast agents or as anti-inflammatory drugs in rheumatoid therapeutics. These products can be used as drugs by general route or by local vascular route in the treatment of certain cancers by chemoembolization consisting in administering an anticancer cancer emulsified in esters of iodized fatty acids which act as vectors for lipophilic tumor cells.

Claims

REVENDICATIONS
1. Esters d'acides gras iodés ou acides gras iodés et leurs dérivés de pureté pharmaceutique, stables, dépourvus d'impuretés toxiques, totalement iodés, ne présentant plus de doubles liaisons, obtenus par action d'un réactif alkylsilylé et d'un iodure alcalin sur des esters d'acides gras ou des acides gras et présentant des propriétés thérapeutiques.1. Esters of iodized fatty acids or iodized fatty acids and their derivatives of pharmaceutical purity, stable, free from toxic impurities, totally iodized, no longer having double bonds, obtained by the action of an alkylsilylated reagent and an iodide alkaline on fatty acid esters or fatty acids and having therapeutic properties.
2. Esters d'acides gras selon la revendication 1, tel par exemple des triglycérides d'acides gras provenant d'huiles végétales, du type huile de colza, huile d'oeillette, huile de soja, huile de carthame, huile d'arachides, huile de pépins de raisin, huile de tournesol, huile de lin, huile de maïs, huile d'olive, huile de sésame, huile de germes de blé, huile de noix de coco, huile de palme et huiles d'origine animale.2. Esters of fatty acids according to claim 1, such as for example triglycerides of fatty acids originating from vegetable oils, of the rapeseed oil type, flaxseed oil, soybean oil, safflower oil, peanut oil , grape seed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil, palm oil and oils of animal origin.
3. Esters d'acides gras selon la revendication 1 tel par exemple, des mélanges d'esters méthyliques d'acides gras provenant d'huiles végétales, du type huile de colza, huile d'oeillette, huile de soja, huile de carthame, huile d'arachides, huile de pépins de raisin, huile de tournesol, huile de lin, huile de maïs, huile d'olive, huile de sésame, huile de germe de blé, huile de noix de coco, huile de palme et huiles d'origine animale. 3. Esters of fatty acids according to claim 1, such as, for example, mixtures of methyl esters of fatty acids originating from vegetable oils, of the rapeseed oil type, flaxseed oil, soybean oil, safflower oil, peanut oil, grape seed oil, sunflower oil, flaxseed oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil, palm oil and palm oil animal origin.
4. Esters d'acides gras selon la revendication 1 , tel par exemple des mélanges d'esters éthyliques d'acides gras provenant d'huiles végétales, tel du type huile de colza, huile d'oeillette, huile de soja, huile de carthame, huile d'arachides, huile de pépins de raisin, huile de tournesol, huile de lin, huile de maïs, huile d'olive, huile de sésame, huile de germe de blé, huile de noix de coco, huile de palme et huiles d'origine animale. 4. Fatty acid esters according to claim 1, such as, for example, mixtures of ethyl esters of fatty acids obtained from vegetable oils, such as rapeseed oil, flaxseed oil, soybean oil, oil. safflower, peanut oil, grape seed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheat germ oil, coconut oil, palm oil and oils of animal origin.
5. Esters d'acides gras selon la revendication 1, tel par exemple des esters méthyliques d'acides gras provenant de l'huile de colza, utilisés comme carburant biologique pour moteur de voitures d'un prix de revient faible.5. Esters of fatty acids according to claim 1, such as for example methyl esters of fatty acids from rapeseed oil, used as biological fuel for car engines at low cost.
6. Acides gras selon la revendication 1, tel par exemple les acides gras du type acide oléique, acide linoléique, acide α-linolénique, acide érucique, acide arachidonique, acide ricinolique.6. Fatty acids according to claim 1, such as for example fatty acids of the oleic acid, linoleic acid, α-linolenic acid, erucic acid, arachidonic acid, ricinolic acid type.
7. Procédé pour l'obtention d'esters d'acides gras iodés selon l'une quelconque des revendications de 1 à 5 caractérisé en ce qu'il consiste à faire réagir un iodure alcalin avec un halogénurealkylsilylé en milieu organique donnant naissance en présence d'eau à de l'acide iodhydrique in situ réagissant avec l'ester ou les esters d'acides gras.7. Method for obtaining iodized fatty acid esters according to any one of claims 1 to 5 characterized in that it consists in reacting an alkaline iodide with a halurealkylsilylated in organic medium giving rise in the presence of water to in situ hydroiodic acid reacting with the ester or esters of fatty acids.
8. Procédé pour l'obtention d'acides gras iodés ou dérivés iodés, selon l'une quelconque des revendications 1 et 6, caractérisé en ce qu'il consiste à faire réagir un iodure alcalin avec un halogénurealkylsilylé en milieu organique donnant naissance en présence d'eau à de l'acide iodhydrique in situ réagissant avec les acides gras ou avec leurs dérivés.8. A method for obtaining iodized fatty acids or iodized derivatives, according to any one of claims 1 and 6, characterized in that it consists in reacting an alkaline iodide with a halurealkylsilylated in organic medium giving birth in the presence water to in situ hydroiodic acid reacting with fatty acids or their derivatives.
9. Procédé pour l'obtention d'esters d'acides gras iodés ou d'acides gras iodés selon l'une quelconque des revendications de 7 et 8 caractérisé en ce qu'il consiste à faire réagir de l'iodure de sodium sur du chlorure de trimethylsilyle ou trimethylchlorosilane dans de l'acétonitrile suivie de l'action de l'eau et d'une addition soit d'esters d'acides gras insaturés, soit d'acide gras insaturés.9. A method for obtaining esters of iodized fatty acids or iodized fatty acids according to any one of claims 7 and 8 characterized in that it consists in reacting sodium iodide on trimethylsilyl chloride or trimethylchlorosilane in acetonitrile followed by the action of water and the addition of either esters of unsaturated fatty acids or of unsaturated fatty acids.
10. Produits iodés selon l'une quelconque des revendications 1 à 6 utilisés pour la préparation de médicaments par voie générale, par exemple comme anti-goitreux à l'état pur ou en combinaison avec des excipients appropriés sous forme de liquide buvable ou ingérable, de gélules ou d'ampoules par exemple.10. Iodized products according to any one of claims 1 to 6 used for the preparation of medicaments by general route, for example as anti-goiter in the pure state or in combination with suitable excipients in the form of drinkable or ingestible liquid, capsules or ampoules for example.
11. Produits selon l'une quelconque des revendications 1 à 6 utilisés pour la préparation de médicaments par voie générale par exemple comme produits de contraste.11. Products according to any one of claims 1 to 6 used for the preparation of medicaments generally, for example as contrast agents.
12. Produits iodés selon l'une quelconque des revendications 1 à 6 utilisés pour la préparation de médicaments par voie générale ou topique, par exemple comme antiinflammatoires en thérapeutiques rhumatoïdes.12. Iodized products according to any one of claims 1 to 6 used for the preparation of medicaments by general or topical route, for example as anti-inflammatory drugs in rheumatoid therapeutics.
13. Produits iodés selon l'une quelconque des revendications 1 à 6 utilisés pour la préparation de médicaments par voie générale ou par voie vasculaire locale, par exemple dans le traitement de certains cancers par chimioembolisation consistant à administrer un anticancéreux émulsionné dans des esters d'acides gras iodés qui jouent le rôle de vecteurs pour les cellules lipophiles tumorales. 13. Iodized products according to any one of claims 1 to 6 used for the preparation of medicaments by general route or by local vascular route, for example in the treatment of certain cancers by chemoembolization consisting in administering an anticancer agent emulsified in esters of iodized fatty acids which act as vectors for lipophilic tumor cells.
PCT/FR1996/001075 1995-07-11 1996-07-10 Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkylsilylated derivatives and alkaline iodides, and pharmacological activities thereof WO1997003038A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
BR9609610-1A BR9609610A (en) 1995-07-11 1996-07-10 esters of iodinated fatty acids, iodinated fatty acids and their derivatives, obtained by iodohydration, involving the introduction of alkylated alkylated derivatives with alkaline iodides and their pharmacological activities
PL96324383A PL185807B1 (en) 1995-07-11 1996-07-10 Iodinated fatty acid esters, iodinated fatty acids and their derivatives, obtained by formation of iodohydrides in presence of alkylosillyl derivatives and alkaline iodides and their pharmacological activity
EP96924964A EP0840720B1 (en) 1995-07-11 1996-07-10 Process for making iodinated fatty acids and derivatives thereof by iodohydrination using alkylsilylated derivatives and alkaline iodides and pharmacological activities thereof
EA199800120A EA001719B1 (en) 1995-07-11 1996-07-10 Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, process fof obtaining thereof and pharmaceutical use
AU65234/96A AU6523496A (en) 1995-07-11 1996-07-10 Iodinated fatty acid esters, iodinated fatty acids and derivtives thereof, produced by iodohydrination using alkylsilylaed derivatives and alkaline iodides, and pharmacological actvities thereof
US08/981,931 US6124357A (en) 1995-07-11 1996-07-10 Iodinated fatty acid esters iodinated fatty acids and derivatives thereof produced by iodohydrination using alkylsilylated derivatives and alkaline iodides and the pharmacological activities thereof
RO98-00028A RO120337B1 (en) 1995-07-11 1996-07-10 Process for preparing iodinated fatty acids, iodinated fatty acid esters and iodinated derivatives thereof and their pharmaceutical uses
AT96924964T ATE249414T1 (en) 1995-07-11 1996-07-10 METHOD FOR THE PRODUCTION OF IODINATED FATTY ACIDS AND THEIR DERIVATIVES BY HYDROIDODINE ACCESSION USING ALKYLSILYL DERIVATIVES WITH ALKALINE IODIDES AND THEIR PHARMACOLOGICAL ACTIVITIES
APAP/P/1998/001180A AP874A (en) 1995-07-11 1996-07-10 Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkysilylated derivatives and alkaline iodides, and pharmacological activities thereof.
DE69629928T DE69629928T2 (en) 1995-07-11 1996-07-10 METHOD FOR THE PRODUCTION OF IODATED FATTY ACIDS AND THEIR DERIVATIVES BY HYDROGEN IODINE ADHESION USING ALKYLSILYL DERIVATIVES WITH ALKALI IODIDES AND THEIR PHARMACOLOGICAL ACTIVITIES
UA98020668A UA56142C2 (en) 1995-07-11 1996-10-07 Iodinated fatty acid or iodinated fatty acid ester or iodinated derivatives thereof, a process for preparing the same
BG102234A BG63802B1 (en) 1995-07-11 1998-02-05 Method for the production of esters of iodinated fatty acids, iodinated fatty acids and their derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR95/08582 1995-07-11
FR9508582A FR2736549B1 (en) 1995-07-11 1995-07-11 ESTERS OF IODINE FATTY ACIDS, IODINE FATTY ACIDS AND DERIVATIVES THEREOF, OBTAINED BY IODOHYDRINATION USING ALKYLSILYL DERIVATIVES WITH ALKALINE IODIDES AND THEIR PHARMACOLOGICAL ACTIVITIES

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WO1997003038A1 true WO1997003038A1 (en) 1997-01-30

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US (1) US6124357A (en)
EP (1) EP0840720B1 (en)
CN (1) CN1077880C (en)
AP (1) AP874A (en)
AT (1) ATE249414T1 (en)
AU (1) AU6523496A (en)
BG (1) BG63802B1 (en)
BR (1) BR9609610A (en)
DE (1) DE69629928T2 (en)
EA (1) EA001719B1 (en)
FR (1) FR2736549B1 (en)
GE (1) GEP20002238B (en)
HU (1) HUP9901340A3 (en)
IN (1) IN185195B (en)
MA (1) MA23935A1 (en)
OA (1) OA10650A (en)
PL (1) PL185807B1 (en)
RO (1) RO120337B1 (en)
TR (1) TR199800031T1 (en)
UA (1) UA56142C2 (en)
WO (1) WO1997003038A1 (en)

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WO2012172192A1 (en) * 2011-06-14 2012-12-20 R.I.Ph Iodinated fatty acid esters containing a minimum of 50 percent of monoiodostearic acid esters or derivatives in the form of a soft capsule or a gel capsule, of use during a nuclear accident

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US6426367B1 (en) * 1999-09-09 2002-07-30 Efa Sciences Llc Methods for selectively occluding blood supplies to neoplasias
FR2891461B1 (en) * 2005-09-30 2010-09-03 Jacques Theron INJECTABLE VISCOUS MEDICINAL PREPARATION COMPRISING ETHANOL AND X-RAY OPAQUE LIPOSOLUBLE COMPOUND
CN101245007B (en) * 2008-03-13 2011-03-23 武汉工程大学 Process for producing iodination vegetable oil fatty acid ethyl ester
CN107287029B (en) * 2016-05-30 2021-04-06 江苏恒瑞医药股份有限公司 Preparation method of iodized vegetable oil fatty acid ethyl ester
CN109251142A (en) * 2017-07-12 2019-01-22 财团法人食品工业发展研究所 Preparation method of iodized fatty acid ethyl ester
CN109251144B (en) * 2017-07-12 2021-06-18 财团法人食品工业发展研究所 Preparation method of iodized fatty acid ethyl ester
CN111194225B (en) * 2017-08-07 2023-01-13 日内瓦大学 Nanoemulsion of iodinated fatty acids for CT imaging
CN110387286A (en) * 2018-04-18 2019-10-29 江苏恒瑞医药股份有限公司 A kind of preparation method of iodized vegetable fatty acids ethyl ester
CN109438240B (en) * 2018-09-10 2022-05-03 季珉 Preparation method of stable iodized linoleate
CN114606055B (en) * 2020-12-08 2024-02-13 成都西岭源药业有限公司 Method for removing unstable iodine combined in iodized vegetable oil fatty acid ethyl ester
EP4380687A1 (en) * 2021-08-02 2024-06-12 Microvention, Inc. Iodinated fatty acids for medical imaging
PL245039B1 (en) * 2022-02-15 2024-04-22 Centrum Badan I Rozwoju Tech Dla Przemyslu Spolka Akcyjna Bioactive candle and method of producing bioactive candle

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2012172192A1 (en) * 2011-06-14 2012-12-20 R.I.Ph Iodinated fatty acid esters containing a minimum of 50 percent of monoiodostearic acid esters or derivatives in the form of a soft capsule or a gel capsule, of use during a nuclear accident
FR2976491A1 (en) * 2011-06-14 2012-12-21 R I P H IODIZED FATTY ACID ESTERS CONTAINING AT LEAST 50 PER CENT OF MONOIODO STEARIC ACID ESTERS OR DERIVATIVES IN THE FORM OF A SOFT CAPSULE OR GELULE, USEFUL IN A NUCLEAR ACCIDENT.

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PL324383A1 (en) 1998-05-25
PL185807B1 (en) 2003-08-29
HUP9901340A2 (en) 1999-09-28
AU6523496A (en) 1997-02-10
DE69629928T2 (en) 2004-07-22
HUP9901340A3 (en) 1999-11-29
RO120337B1 (en) 2005-12-30
CN1143067A (en) 1997-02-19
MA23935A1 (en) 1997-04-01
BR9609610A (en) 2002-05-07
BG63802B1 (en) 2003-01-31
IN185195B (en) 2000-12-02
CN1077880C (en) 2002-01-16
OA10650A (en) 2002-09-18
TR199800031T1 (en) 1998-05-21
MX9800322A (en) 1998-09-30
EP0840720B1 (en) 2003-09-10
EA001719B1 (en) 2001-08-27
GEP20002238B (en) 2000-09-25
FR2736549B1 (en) 1997-10-10
US6124357A (en) 2000-09-26
DE69629928D1 (en) 2003-10-16
ATE249414T1 (en) 2003-09-15
BG102234A (en) 1998-09-30
AP874A (en) 2000-09-13
EA199800120A1 (en) 1998-10-29
FR2736549A1 (en) 1997-01-17
EP0840720A1 (en) 1998-05-13
UA56142C2 (en) 2003-05-15

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